Review of the VOXILAPREVIR PATENT LANDSCAPE: A scoping report

March 2017 CONTENTS

© 2017 World Health Organization (Acting as the host organization for the Secretariat of UNITAID)

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.

This report was prepared by Andrew Brown and Amel Garbi (Pharmathen) with input from Karin Timmermans (UNITAID). All reasonable precautions have been taken by the authors and the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall UNITAID or the World Health Organization be liable for damages arising from its use. CONTENTS

Abbreviations 4 I. Introduction 5 II. Methodology 6 III. Background 7 Hepatitis C virus 7 Voxilaprevir 9 IV. Overview of voxilaprevir patents 10 V. Analysis of voxilaprevir patents/applications 12 ANNEX 1. VOXILAPREVIR patent situation in countries 27 4

ABBREVIATIONS I.

DAA direct-acting antiviral

EPO European Patent Office

HCV hepatitis C virus

HIV human immunodeficiency virus

NS non-structural

PCT Patent Cooperation Treaty

PEG-interferon Pegylated interferon

RNA ribonucleic acid 5

I. INTRODUCTION

Hepatitis C is a major global health These DAAs generate cure rates that problem; some 130−150 million people approach or exceed 90 per cent. Some worldwide are chronically infected with combination regimens may have pan- the hepatitis C virus (HCV). It is estimated genotypic efficacy, which would simplify that, worldwide, 2.9 million people treatment and monitoring. One compound are coinfected with HIV and HCV. Each of interest is Gilead’s investigational year, approximately 700,000 people compound GS-9857, or voxilaprevir. die of HCV-related liver disease, and evidence indicates that the HCV burden In view of its potential role in future is increasing.1,2,3 While the HCV epidemic treatment, this report explores the patent is global in scope, the HCV burden varies landscape of voxilaprevir. considerably between countries.

The virus has six primary genotypes. Genotypes 1 and 3 are the most prevalent, accounting respectively for 46 per cent and 30 per cent of HCV cases worldwide. Together, genotypes 2, 4 and 6 represent around 23 per cent of HCV cases, while genotype 5 accounts for less than 1 per cent.4

Efforts to treat HCV have historically been hampered by suboptimal and inadequate treatments. However, the development of direct-acting antivirals (DAAs) has dramatically improved the prospects for HCV treatment and has altered the standard of care. Several new DAAs that do not require Pegylated interferon (PEG- interferon) have been launched since late 2013, and a number of other DAAs are in development.

1. Hepatitis C factsheet. Geneva: World Health Organization; July 2016 (http://www.who.int/mediacentre/factsheets/fs164/en/, accessed 29 January 2017).

2. Global health sector strategy on viral hepatitis 2016−2021. Geneva: World Health Organization; 2016.

3. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385(117−71).

4. Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, Pybus OG et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology. 2014;61(1):77−87. 6

II. METHODOLOGY III.

Relevant patents and patent applications were updated in February 2017. were identified by searching patent and non-patent databases, namely: SciFinder, Caveat: It is important to note that the PatBase, TotalPatent and Google Patents. patent status of a given product in a given Searches were carried out using keywords, country may change and that data may semantic searches, International Patent therefore become outdated. It is advisable Classification (IPC) searches, chemical always to check with the relevant national structure searches and combinations or regional patent office for the most thereof. up-to-date information on the status of a given patent or patent application. For each of the most relevant patent and/ or applications, the equivalents were This report was prepared by Andrew identified (INPADOC family) and the legal Brown and Amel Garbi (Pharmathen), with status of each of the equivalents was input from Karin Timmermans (UNITAID). checked on the websites of the relevant The patent searches were conducted by patent offices. The countries listed in Amel Garbi. Pascale Boulet updated the Annex 1 represent those for which data are searches for Patent 2 and 3. available. Peter Beyer and Pascale Boulet reviewed The searches were performed in December a draft version of this report, and provided 2015. Information for Patent 1 was valuable input and suggestions. complemented with data from Form 3 submitted to the Indian Patent Office in April 2016. Searches for Patents 2 and 3 7

III. BACKGROUND

Hepatitis C virus (core, E1 and E2), the ion channel protein p7, and six non-structural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) The hepatitis C virus is a small (55−65 nm), (see Figure 1). Each of these proteins plays enveloped, positive-sense, single-stranded a role in HCV entry, infection, replication RNA virus of the Flaviviridae family. The or maturation and is therefore a potential virus consists of three structural proteins target for medicines.

Figure 1. Hepatitis C virus RNA

9600 nt bases

Gene encoding precursor polyprotein

5’ NTR Structural proteins Non-structural proteins 3’ NTR

p22 gp35 gp70 p7 p23 p70 p8 p27 p56/58 p68

C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B

Envelope transmembrane co-factors RNA glycoproteins protein polymerase

Nucleocapsid proteases interferon resisting RNA helicase protein

Adapted from Graham Colm. 8

DAAs block viral production by directly for boceprevir or telaprevir with PEG- inhibiting one or more steps of the HCV interferon and ribavirin were higher than replication cycle. DAAs can be divided those of PEG-interferon and ribavirin, into categories – notably NS3/NS4A but side-effects could be severe and serine protease inhibitors, NS5A complex some patients were obliged to stop the inhibitors and NS5B RNA polymerase treatment. inhibitors (both nucleoside and non- nucleoside). Second-wave and second-generation HCV protease inhibitors appear to hold promise HCV NS3 (serine) protease is one of the as they prove to be more potent, less prone most, if not the most, intensively studied to resistance, more convenient (most are anti-HCV targets, possibly because it is one once-daily) and more tolerable than the of the best-characterized HCV enzymes earlier drugs in this class. One of these but also because of the successful use newer protease inhibitors is voxilaprevir. of protease inhibitors as anti-HIV agents. NS3/4A protease inhibitors work by blocking a viral enzyme (protease) that enables the hepatitis C virus to survive and In December 2016, Gilead submitted a replicate in host cells. new drug application to the US Food and Drug Administration for the fixed-dose Several inhibitors of HCV NS3/4A protease combination sofosbuvir/velpatasvir/ have been identified and developed. voxilaprevir for treatment of HCV The first-generation protease inhibitors genotypes 1−6.5 In January 2017, the (boceprevir and telaprevir) were approved European Medicines Agency reportedly for administration in combination with granted accelerated assessment for PEG-interferon and ribavirin. Cure rates sofosbuvir/velpatasvir/voxilaprevir.6

5 Gilead submits new drug application to U.S. Food and Drug Administration for the investigational single tablet regimen sofosbuvir/velpatasvir/ voxilaprevir. Business Wire. 8 December 2016.

6 European Medicines Agency Validates Gilead’s Marketing Authorization Application for Investigational Chronic Hepatitis C Therapy Sofosbuvir/ Velpatasvir/Voxilaprevir (SOF/VEL/VOX). Business Wire. 20 January 2017. 9

Voxilaprevir against all genotypes. It also appears to have an improved resistance profile compared to other HCV protease inhibitors Voxilaprevir (formerly known as GS-9857) (PIs).7 is a novel, fluorinated macrocyclic HCV NS3/4A protease inhibitor in clinical The chemical structure of voxilaprevir is development that is showing efficacy shown in Figure 2.

Figure 2. Structure of voxilaprevir

Chemical name: (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-{(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl) sulfonyl]carbamoyl}cyclopropyl}-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5 ,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa [18,19][1,10,3,6] dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide.

Molecular formula:

C40H52F4N6O9S.

Molecular weight: 766.9034 g/mol.

CAS registry number: 1535212-07-7.

7 Gilead Sciences. Evaluation of transporter and cytochrome P450-mediateddrug-drug interactions with the pan-genotypic HCV NS3/4A protease inhibitor voxilaprevir (GS-9857) or sofosbuvir/velpatasvir/voxilaprevir and phenotypic probe drugs. Presentation at the 17th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, June 2016, Washington DC, quoting Taylor JG et al., EASL 2015, poster 899. 10

OVERVIEW OF IV. VOXILAPREVIR PATENTS

Four patents and/or patent applications cirrhosis by administering to the subject an related to voxilaprevir appear to be the effective amount of sofosbuvir. In various most relevant. These patents/applications methods, sofosbuvir can be concomitantly include the patent/application covering administered with at least one additional the compound per se. Patents/ anti-HCV agent. Non-limiting examples applications have also been identified include velpatasvir and voxilaprevir. that relate to improved processes for the preparation of voxilaprevir and key This application should be monitored intermediates, to new crystalline form(s) of because some claims may become voxilaprevir and their use in compositions, constraining after amendments and and to combinations and methods of use. depending on the country.

Patent 1 is the compound patent. It would At the time of writing, the majority of be likely to block the production, import, the patents/applications identified, marketing and use of generic versions of with the exception of Patent 1, were voxilaprevir in countries where it is in force. Patent Cooperation Treaty (PCT) patent applications that had not yet entered Patents 2 and 3, which respectively national phases. relate to crystalline forms of voxilaprevir and to processes for the preparation of Patent 1 had entered several national voxilaprevir and key intermediates, are phases; the INPADOC family members are not considered as constraining patents, listed in Annex 1. All applications were provided that generic manufacturers still under examination; they should be are able to use a different crystalline monitored. form and/or prepare voxilaprevir via a different synthetic route using different Table 1 gives a brief overview of the most intermediates. relevant patents and/or applications. More extensive information on the scope Patent 4 relates to methods of treating of protection is provided in section V and hepatitis C virus infection in a subject with Annex 1. 11

Table 1. Overview of key patents on voxilaprevir

PCT application Filing number Applicants date Comments

PATENT 1 WO2014/008285 Gilead Sciences 02 July 2013 Broad compound patent; (USA) claims voxilaprevir generically and specifically. Likely to be constraining for generic entry. PATENT 2 WO2015/100144 Gilead Sciences 18 December 2014 Crystalline forms of voxilaprevir. (USA) Provided that generic manufacturers source a different form, this patent will not constrain generic entry. PATENT 3 WO2015/100145 Gilead Sciences 18 December 2014 Process for the preparation of (USA) voxilaprevir and key intermediates. Provided that generic manufacturers prepare voxilaprevir by a different synthetic route, via different intermediates, this patent will not constrain generic entry. PATENT 4 WO2015/084741 Gilead 01 December 2014 Methods of treating HCV infection in Pharmasset LLC subjects with cirrhosis, comprising (USA) administration of sofosbuvir (1−48 weeks) (100−800 mg) + optionally at least one additional anti-HCV agent (e.g. velpatasvir, voxilaprevir). 12

ANALYSIS OF VOXILAPREVIR V. PATENTS/APPLICATIONS

PATENT 1 Title: Inhibitors of hepatitis C virus WO 2014/008285 (Gilead Sciences (USA), filed 02 July 2013)

Summary

The PCT application, a broad compound (I) patent, claims compounds of Markush formula (I), and the selection compounds of general formulae (II), (III) and (IV), and pharmaceutically acceptable salts thereof.

Voxilaprevir falls within the scope of compounds of general formula (IV). It is generically claimed at claim 1 of the PCT (I) application and is specifically claimed at claims 21 and 22.

This patent would be likely to block generic market entry in the countries where it is in force. (I)

Description

The PCT application relates to compounds of Markush formula (I) and the selection compounds of general formulae (II), (I) (III) and (IV), or stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salts thereof, depicted below. 13

The disclosed compounds are claimed these compounds, or salts thereof, may be to be useful as inhibitors of the HCV the primary active therapeutic agent and, NS3 protease, and thus useful for the when appropriate, may be combined with prophylactic or therapeutic treatment of at least one additional therapeutic agent HCV infection, either as compounds or as including, but not limited to, another HCV pharmaceutical composition ingredients. antiviral (e.g. interferon, ribavirin analog, HCV NS3 protease inhibitor, NS4B inhibitor, NS5A A large number of compounds has been inhibitor, NS5B inhibitor, alpha-glucosidase tested and has been shown to inhibit inhibitor, a non-nucleoside inhibitor), a multiple genotypes of the virus. hepatoprotectant or another drug for treating hepatitis C virus infection (claim 83). The PCT application has 84 claims, of which 18 are independent. A method for treating HCV infection comprising administration of a The claims are directed to compounds therapeutically effective amount of the (I), (II), (III) and (IV) or stereoisomers, compounds of any of claims 1−76 or a salt or mixtures of stereoisomers or thereof or pharmaceutical compositions of pharmaceutically acceptable salts thereof claim 77 are also claimed (claim 78). (claims 1, 29, 37 and 42). The application finally claims the Compounds which are selections of the use of the claimed compounds and compounds of Markush and general pharmaceutical compositions for the formulae are specifically claimed prophylactic or therapeutic treatment of (claims 21−28 and claim 76 [list of 97 hepatitis C virus (claim 81), and for the compounds]). manufacture of a medicament for treating hepatitis C virus infection (claim 82). Voxilaprevir falls within the scope of compounds of general formula (IV), Processes for the preparation of the compounds comprising a quinoxaline claimed compounds and their key heterocycle, which is connected to the intermediates are disclosed. General proline moiety through the carbocyclic and specific schemes, procedures and part of the fused heterocycle. examples are provided describing the Voxilaprevir is generically claimed at claim synthesis of the claimed compounds as 1 of the PCT application, and specifically well as the intermediates used to prepare claimed at claims 21 and 22. Claim 21 the compounds. refers to voxilaprevir or a stereoisomer or mixture of stereoisomers or salts thereof (no stereochemistry mentioned); Observations voxilaprevir as a single stereoisomer is claimed at claim 22. Some of the claimed compounds, namely Also claimed are pharmaceutical the ones covered by the scope of claims compositions comprising a compound 1 and 21−28, were considered novel and of any of the claims 1−76, or salts thereof, inventive by the International Searching and a pharmaceutically acceptable Authority (European Patent Office, or EPO) excipient (claim 77). as none of the prior art discloses any compounds which are structurally close to As pharmaceutical composition ingredients, these compounds. 14

According to the International Searching examiner. Authority, the compounds that fall within the scope of claims 29−75 lack novelty After these amendments, the application over the prior art (i.e. WO 2007/016441 A1 still covers voxilaprevir per se, [Merck, filed 28 July 2006]) and are not pharmaceutical compositions comprising adequately supported by the description. it – either as a sole active ingredient or, when appropriate, combined with at Upon entry into the European phase least one additional therapeutic agent, (17 December 2014), and following the including but not limited to, other HCV comments made by the International antivirals – and its methods of use. Searching Authority (20 January 2015), the The application is still under examination applicants submitted a set of amended and should be monitored. claims (23 March 2015). The amended claims have been limited to the subject matter of This patent, when granted, would be original claims 1−28 for which both novelty likely to block generic market entry in the and inventive step were conceded by the countries where it is in force. 15

PATENT 2 Title: Crystalline forms of a macrocyclic HCV NS3 inhibiting tripeptide WO 2015/100144 (Gilead Sciences (USA), filed 18 December 2014)

Summary diffractometer using Cu-Kα radiation. In addition to the X-ray powder diffraction patterns, the differential This PCT application relates to crystalline scanning calorimetry (DSC) curves, the forms of voxilaprevir. thermogravimetric analysis (TGAs) and the dynamic vapour sorptions (DVS) of the This patent is not considered as disclosed forms are given. constraining for generic market entry, provided that the generic manufacturer The application discloses crystalline forms uses a different crystalline form. I−XXI, but only crystalline forms I−XII are claimed. As mentioned above, the PCT application also discloses crystalline forms Description of salts or co-crystals of voxilaprevir but does not claim them.

The PCT application discloses: Another embodiment of the invention is directed to a composition comprising • 17 crystalline voxilaprevir one or more of voxilaprevir forms solvate forms (such as the ethyl I−XXI together with one or more acetate, isopropyl acetate, pharmaceutically acceptable carriers ethanol, isopropanol, methanol, or excipients. Additionally, a method tetrahydrofuran, 2-methyl for treating a subject suffering tetrahydrofuran, toluene, methyl from hepatitis C virus comprising tert-butyl ether, dimethyl acetamide administration to the subject of a and dimethylformamide, but also the therapeutically effective amount of hydrates [hemihydrate, dihydrate, any one of voxilaprevir forms I−XXI is tetrahydrate]); provided. • 4 crystalline voxilaprevir anhydrous forms; Pharmaceutical compositions comprising and a compound selected from the claimed • 14 crystalline forms of salts or co- crystalline forms (i.e. forms I−XII only) and crystals of voxilaprevir (such as the a pharmaceutically acceptable excipient sodium, potassium, meglumine, are claimed (claim 33). piperazine, choline, dimethyl aminoethanol, 1-(2-hyrdoxyethyl) In yet another embodiment, the present pyrrolidine, lysine and arginine). application discloses pharmaceutical compositions comprising a voxilaprevir These crystalline forms are characterized crystalline form, selected from disclosed by peaks from the X-ray powder forms I−XXI, in combination with at least diffractogram, as determined on a one additional therapeutic agent. The 16

additional therapeutic agent includes, Observations without limitation, one or more of the following: interferons, ribavirin and analogs, NS3 protease inhibitors, The PCT application has not yet entered NS5A inhibitors, NS5B inhibitors, any national phase. alpha-glucosidase-1 inhibitors, hepatoprotectants, non-nucleoside The PCT application has 47 claims, of inhibitors of HCV, nucleosides analogs which 26 are independent. and other drugs for treating HCV infection. The additional antiviral agent The written opinion of the International should preferably not be an interferon, Searching Authority (EPO), published on ribavirin or a ribavirin analog. Even 02 July 2015, found that all claims were more preferably, the pharmaceutical novel and involve an inventive step. composition should include voxilaprevir The International Searching Authority crystalline form and one or more of an noted that the application suffers from NS5A inhibitor and/or an NS5B inhibitor. lack of clarity, chiefly because the claimed A method of treating a subject with HCV crystalline forms are defined by only three infection is claimed (claim 34) comprising or four peak positions. This is insufficient administration to the subject of a for a person skilled in the art; the 10 therapeutically effective amount of one strongest reflections are generally required of the claimed crystalline forms and a for complete characterization of a given pharmaceutically acceptable excipient. This polymorph. method can, optionally, further include the This patent is not considered as administration to the subject of at least one constraining for generic market entry further anti-HCV agent (claim 35). provided that the generic manufacturer Finally, processes for making the claimed uses a different crystalline form. crystalline forms I−XII are claimed (claims 36−47). 17

PATENT 3 Title: Synthesis of a macrocyclic HCV NS3 inhibiting tripeptide WO 2015/100145 (Gilead Sciences (USA), filed 18 December 2014)

Summary Route I: The process for the preparation of The PCT application provides and voxilaprevir, or a co-crystal or a salt claims processes for the preparation of thereof, comprises: voxilaprevir. The application also provides and claims compounds and processes for (a) contacting a compound (III), or a co- the preparation of key intermediates. crystal or salt thereof, with a compound (IV) or a co-crystal or salt thereof under This patent is not considered as O-arylation conditions to provide a constraining for generic market entry, compound (V) or a co-crystal or salt

provided that the generic producer thereof, wherein R is C1-6 alkyl, PG is a manufactures voxilaprevir using different protective group and R1 is a leaving group; key intermediates and a different synthetic route for the preparation of voxilaprevir.

Description

The application provides, in a first embodiment, a process for making compound (I) (voxilaprevir), or a co-crystal or salt thereof, according to Route I (claim 5 of the PCT application):

(b) subjecting compound (V), or a co- crystal or salt thereof, to N-deprotection conditions to provide compound (VI) or a co-crystal or salt thereof; 18

(c) contacting compound (VI), or a co- (e) hydrogenating compound (IX), or a co- crystal or salt thereof, with a compound crystal or salt thereof, in the presence of (VII) or a co-crystal or salt thereof under a catalyst to provide a compound (X) or a amide coupling conditions to provide co-crystal or salt thereof; a compound (VIII) or a co-crystal or salt thereof;

(f) hydrolysing compound (X), or a co- crystal or salt thereof, to provide compound (XI) or a co-crystal or salt thereof;

(d) performing ring closing metathesis of compound (VIII), or a co-crystal or salt thereof, to provide compound (IX) or a co- crystal or salt thereof;

(g) contacting compound (XI), or a co- crystal or salt thereof, with compound (XII) or a co-crystal or salt thereof under amide coupling conditions to provide voxilaprevir.

In relation to Route I, the application additionally provides processes for the preparation of the key intermediates (V), (VI), (VIII) and (IX). 19

The process for the preparation of key is a precursor of compound (VII), are also compound (V), or a co-crystal or salt claimed (claims 28, 29, 30, 31 and 32). thereof, comprises contacting compound (III) or a co-crystal or salt thereof with a compound (IV) or a co-crystal or salt thereof under O-arylation conditions to provide compound (V) or a co-crystal or salt thereof, wherein R is C1-6 alkyl, PG is a protective group and R1 is a leaving group (see step a of process Route I and claim 1).

The process for the preparation of key compound (VI), or a co-crystal or salt thereof, comprises subjecting compound (V) or a co-crystal or salt thereof, to N-deprotection conditions to provide the compound (VI) or a co-crystal or salt thereof, wherein R is C1-6 alkyl and PG is a protective group (see step b of process Route I, and claim 2).

The process for the preparation of key compound (VIII), or a co-crystal or salt thereof, comprises contacting compound (VI) or a co-crystal or salt thereof with a compound (VII) or a co-crystal or salt thereof, under amide coupling conditions to provide compound (VIII) or a co-crystal or salt thereof, wherein R is C1-6 alkyl (see step c of process Route I and claim 3).

The process for the preparation of key compound (IX), or a co-crystal or salt thereof, comprises performing ring closing metathesis of compound (VIII) or a co-crystal or salt thereof to provide compound (IX) or a co-crystal or salt thereof, wherein R is C1-6 alkyl (see step d of process Route I and claim 4).

Key compounds (IV), (V), (VI), (VII) and (VIII) are claimed per se (claims 16, 17, 18, 19 and 20 respectively).

Additionally, key compounds (IV-a), (IV-b), (IV-c) and (IV-d), which are precursors of compound (IV), wherein R1 is a leaving group (e.g. Cl), and compound M3, which 20

Finally, a process for the preparation of Route II: compound (V-v), precursor of compound (XII), is claimed (claim 15). The process for the preparation of voxilaprevir, or a co-crystal or salt thereof, comprises:

(a) contacting a compound (III), or a co- crystal or salt thereof, with a compound (IV) or a co-crystal or salt thereof under O-arylation conditions to provide compound (V) or a co-crystal or salt

Route I differs from the prior art in that thereof, wherein R is C1-6 alkyl, PG is a the ring-closing metathesis step occurs protective group and R1 is a leaving group; at a different position, providing higher efficiency and higher overall yield.

In another embodiment, the application provides a further process for making voxilaprevir, or a co-crystal or a salt thereof, according to Route II (claim 9 of the PCT application).

(b) contacting compound (V), or a co- crystal or salt thereof, with an acid under N-deprotection conditions to provide compound (VI) or a co-crystal or salt thereof; 21

(c) contacting compound (VI), or a co- (f) hydrogenating compound (XIX), or a crystal or salt thereof, with a compound co-crystal or salt thereof, in the presence (VII) or a co-crystal or salt thereof under of a catalyst to provide compound (XI) or a amide coupling conditions to provide co-crystal or salt thereof; compound (VIII) or a co-crystal or salt thereof;

(g) contacting compound (XI), or a co- crystal or salt thereof, with a compound (XII) or a co-crystal or salt thereof under amide coupling conditions to provide voxilaprevir or a co-crystal or salt thereof. (d) hydrolysing compound (VIII), or a co-crystal or salt thereof, to provide compound (XVIII) or a co-crystal or salt thereof;

(e) performing ring-closing metathesis of compound (XVIII), or a co-crystal or salt thereof, in the presence of a catalyst to In relation to Route II, the application provide compound (XIX) or a co-crystal or additionally provides processes for the salt thereof; preparation of the key intermediates (XVIII), (XIX) and (XI).

The process for the preparation of key compound (XVIII), or a co-crystal or salt thereof, comprises hydrolyzing compound (VIII) or a co-crystal or salt thereof to provide compound (XVIII) or a co-crystal or salt thereof, wherein R is

C1-6 alkyl (see step d of process Route II and claim 6). 22

The process for the preparation of key Route III: compound (IX), or a co-crystal or salt thereof, comprises performing ring-closure The process for the preparation of metathesis of compound (XVIII) or a co- voxilaprevir, or a co-crystal or a salt crystal or salt thereof in the presence of thereof, comprises: a catalyst to provide compound (XIX) or a co-crystal or salt thereof (see step e of (a) contacting a compound (XIII), or a co- process Route II, and claim 7). crystal or salt thereof, with a compound (XIV) or a co-crystal or salt thereof under The process for the preparation of cross-metathesis conditions to provide key compound (XI), or a co-crystal or compound (XV) or a co-crystal or salt

salt thereof, comprises hydrogenating thereof, wherein R is C1-6 alkyl and PG is a compound (XIX) or a co-crystal or salt protective group; thereof in the presence of a catalyst to provide compound (XI) or a co-crystal or salt thereof (see step f of process Route II and claim 8).

Key compounds (XVIII) and (XIX) are claimed per se (claims 26 and 27 respectively).

Route II differs from Route I in that steps (d), (e) and (f) are different. In Route I, compound (VIII) was first submitted to ring-closing metathesis, then to hydrogenation and then to hydrolization reactions; in Route II, compound (VIII) is first hydrolyzed to provide compound (XVIII) which is then subjected to ring-

closure metathesis to give compound (XIX) which is hydrogenated to give compound (XI).

In yet another embodiment, the application provides a further process for making voxilaprevir, or a co-crystal or a salt thereof, according to Route III (claim 14 of the PCT application). 23

(b) hydrogenating compound (XV), or a (e) hydrolysing compound (X), or a co-crystal or salt thereof, in the presence co-crystal or salt thereof, to provide a of a catalyst to provide compound (XVI) or compound (XI) or a co-crystal or salt a co-crystal or salt thereof; thereof;

(c) subjecting compound (XVI), or a co- (f) contacting compound (XI), or a co- crystal or salt thereof, to N-deprotection crystal or salt thereof, with compound (XII) conditions to provide compound (XVII) or a or a co-crystal or salt thereof under amide co-crystal or salt thereof; coupling conditions to provide voxilaprevir or a co-crystal or salt thereof.

In relation to Route III, the application additionally provides processes for the preparation of the key intermediates (XV), (XVI), (XVII) and (X). (d) contacting compound (XVII) with an amide coupling agent under lactamization Route III differs from Route I and Route conditions to give compound (X) or a co- II in that the process starts with different crystal or salt thereof; starting compounds (i.e compounds (XIII) and (XIV)) and thus proceeds via different intermediates until the preparation of key compound (XI), which at the final step is contacted with compound (XII) to provide the desired compound (voxilaprevir).

The process for the preparation of key compound (XV), or a co-crystal or salt thereof, comprises contacting a compound (XIII) or a co-crystal or salt thereof with a compound (XIV) or a co- crystal or salt thereof, wherein R is C1-6 24

alkyl and PG is a protective group, under Observations cross-metathesis conditions to provide compound (XV) or a co-crystal or salt thereof (see step a of process Route III and The PCT application has not yet entered claim 10). any national phase.

The process for the preparation of The PCT application has 32 claims, all of key compound (XVI), or a co-crystal or which are independent. salt thereof, comprises hydrogenating compound (XV) or a co-crystal or salt As described above, the PCT application thereof in the presence of a catalyst to discloses and claims three different provide compound (XVI) or a co-crystal or routes for the preparation of voxilaprevir. salt thereof (see step b of process Route III, Additionally, the application discloses and claim 11). and claims novel key intermediates and processes for their preparation. The process for the preparation of key compound (XVII), or a co-crystal or salt The International Search Report, issued thereof, comprises subjecting compound by the International Searching Authority (XVI) or a co-crystal or salt thereof to (EPO), mentions lack of unity of invention; it N-deprotection conditions to provide considers that there are five (5) inventions: compound (XVII) or a co-crystal or salt thereof (see step c of process Route III and 1. claims 1−14, 16−18, 20 and 22−28; claim 12). 2. claim 15, directed at the process for the preparation of compound V-v; The process for the preparation of key 3. claims 19 and 21, directed at compound (X), or a co-crystal or salt compounds VII and XIII per se; thereof, comprises contacting compound 4. claim 29, directed at compound M3 (XVII) or a co-crystal or salt thereof with an per se; and amide coupling agent under lactamization 5. claims 30−32 which are directed to conditions to give compound (X) or a compounds Iva, Iv-b and IV-c. co-crystal or salt thereof (see step d of process Route III and claim 13). The written opinion of the International Searching Authority, published on 2 July Key compounds (XIII), (XIV), (XV), (XVI) and 2015, has been established only with (XVII) are claimed per se (claims 21, 22, 23, respect to invention 1 (i.e. claims 1−14, 24 and 25 respectively). 16−18, 20 and 22−28). These claims were found to be novel, to involve an inventive step and to be industrially applicable.

This patent is not considered as constraining for generic market entry, provided that the generic supplier manufactures voxilaprevir by a route different from the claimed ones and via different key intermediates. 25

PATENT 4 Title: Methods of treating hepatitis C virus infection in subjects with cirrhosis WO 2015/084741 (Gilead Pharmasset (USA), filed 01 December 2014).

Summary include, without limitation, interferons and their analogues, ribavirin and its analogues, NS5A inhibitors (e.g. compound This application relates to methods of A.1: ledispavir; compound A.2: velpatasvir; treating HCV infection in a subject with compound A.4: ombitasvir), NS5B cirrhosis, comprising administration of an polymerase inhibitors (e.g. compound A.5: effective amount of sofosbuvir, alone or in radalbuvir [GS-9669]), protease (NS3, NS3/4) combination with another anti-HCV agent. inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, TLR-7 agonists, The method may further include the cyclophillin inhibitors, HCV IRES inhibitors, concomitant administration of at least pharmacokinetic enhancers (see pp. 8−9 one additional anti-HCV agent; preferably [description] of the PCT application). selected from ribavirin, NS3 protease inhibitors (e.g. voxilaprevir), NS5A (e.g. In a preferred embodiment, the additional velpatasvir) and NS5B inhibitors. therapeutic agent used in combination is an HCV NS3 protease inhibitor; non- The claims to the combinations are only limiting examples including the following dependent claims. compounds:

This application may need to be monitored, as some claims might become constraining for generic market entry after amendments (depending on the country).

Description

This application describes various methods of treating HCV infection in a subject with cirrhosis.

The first method for treating HCV infection in a subject with cirrhosis comprises the administration to the subject of an effective amount of sofosbuvir (claim 1). Sofosbuvir may be administered to the subject with cirrhosis for a duration ranging from about 1 week to about 48 weeks (preferably 4, 8, 12, 24 or 48 weeks).

In various methods, sofosbuvir can be concomitantly administered with at least one additional anti-HCV agent. Examples of additional anti-HCV agents are given; these 26

The first structure corresponds to to the subject an effective amount of voxilaprevir (designated as Compound ribavirin. A.9 at [0051] in the description). The second structure corresponds to GS-9451 2. Claims 11−20: directed to a method (vedroprevir) (designated as Compound of treating HCV infection in a subject ANNEX 1. A.10 at [0052] in the description), and The with cirrhosis comprising the provision third structure corresponds to GS-9256 to the subject of the 5’-mono-, di- or (designated as Compound A.11 at [0053] in triphosphate metabolite of Compound the description). 1 (sofosbuvir).

Various methods are disclosed but only 3. Claims 1−5, 21−23 and 25 (all partially): some of them are claimed. These include directed to a method of treating HCV the methods of claim 1 or claim 11, further infection in a subject with cirrhosis including administration of at least one comprising administration to the additional anti-HCV agent to the subject subject of an effective amount of (dependent claim 21), wherein the Compound 1 (sofosbuvir) and additional anti-HCV agent is selected from Compound A.1 (ledipasvir). NS3 protease inhibitor, NS5A inhibitors and NS5B polymerase inhibitors (dependent 4. Claims 1−5, 21, 22 and 25 (all partially): claim 22), preferably Compound A.1: directed to a method of treating HCV ledispavir (GS-5885) (dependent claim 23) infection in a subject with cirrhosis or compound A.2: velpatasvir (GS-5816) comprising administration to the (dependent claim 24), and wherein the subject of an effective amount of subject has less than about 25 IU/ml of Compound 1 (sofosbuvir) and HCV RNA 2−24 weeks after the end of the Compound A.2 (velpatasvir). treatment (dependent claim 25). 5. Claims 1−5, 21, 22 and 25 (all partially): In other words, voxilaprevir is covered in directed to a method of treating HCV general terms by dependent claims 21 and infection in a subject with cirrhosis 22 but it is not specifically claimed. comprising administration to the subject of an effective amount of Compound 1 (sofosbuvir) and one additional anti-HCV agent other than Observations ribavirin, Compound A.1 (ledpasvir) or Compound A.2 (velpatasvir). During the search and substantive Only the first invention was subjected to examination of the PCT procedure, the search and examination. According to the International Searching Authority (EPO) International Searching Authority, this determined that the application lacked first invention is not novel and lacks an unity. The Authority considered that five inventive step in view of existing prior art. inventions were covered by the claims, as follows: The non-searched “inventions” (inventions 2−5) may be the subject of one or 1. Claims 6−10 (completely), 1−5 (partially) more divisional applications after the and 21−25 (partially): directed to a application has entered the regional phase method of treating HCV infection in before the EPO. a subject with cirrhosis comprising the administration to the subject of an effective amount of Compound 1 (sofosbuvir); the method further includes concomitantly administering 27

VOXILAPREVIR ANNEX 1. PATENT SITUATION IN COUNTRIES

The INPADOC patent family members for each of the four patents/ applications are listed in the table below.

The equivalents were identified (INPADOC family) and, where possible, the legal status of each equivalent was checked on the websites of the relevant patent offices.

Expiry dates in countries that offer patent term extension should be checked. If voxilaprevir is approved for use, it is likely that the originator will apply for the patent term to be extended; countries that offer extension/ restoration of the patent term include the members of the European Union, Japan and the USA.

Patent 1 Patent 2 Patent 3 Patent 4

WO2014008285A WO2015100144A WO2015100145A WO2015084741A1 Appl. N°: PCT/ Appl. N°: PCT/ Appl. N°: PCT/ Appl. N°: PCT/ US2013/049119 US2014/071310 US2014/071319 US2014/067965 Applicants Gilead Sciences (USA) Gilead Sciences (USA) Gilead Sciences (USA) Gilead Pharmasset (USA) Filing date 02 July 2013 18 December 2014 18 December 2014 01 December 2014 Title Inhibitors of hepatitis C Crystalline forms of a Synthesis of a macrocyclic Methods of treating virus macrocyclic HCV NS3 HCV NS3 inhibiting hepatitis C virus infection inhibiting tripeptide tripeptide in subjects with cirrhosis Subject Basic compound patent. Crystalline solvates, Processes for the Methods of treating HCV matter Generic and specific including the hydrates preparation of key infection in subjects with compound claim. and anhydrous crystalline intermediates and cirrhosis comprising forms of voxilaprevir and for the preparation of administration of processes for making voxilaprevir. New key sofosbuvir plus, them; compositions intermediates compounds optionally, at least comprising them and are claimed per se. one additional anti- method for treating HCV HCV agent (examples patient by administration include velpatasvir and of said crystalline voxilaprevir). forms either alone or in combination with at least one anti-HCV agent. Priority data US61/667,806: US 61/920,427: US 61/920,446: US 61/910,631: 03 July 2012 23 December 2013 23 December 2013 02 December 2013 US61/798,524: 15 March 2013 28

Patent 1 Patent 2 Patent 3 Patent 4

Patent status African 201408166D0 - - - Regional Status not available Intellectual Patent Office* Argentina 091661A1 - - - Under examination Australia 2013286729B2 2014370124A1 2014370125A1 - Granted Expiry: 02 July 2033 Bolivia SP-00204-2013 # - - - Brazil 1120140330808 # - - - Canada 2877005A1 2934049A1 2934537A1 - Request for examination (12 November 2015) Chile 3634-2014 # - - - China 104540832A - 105849118A - Request for examination Request for examination (22 July 2015) (7 September 2016) China, Hong - - - Kong SAR Colombia 7160104A2 - - - Status not available Costa Rica 2015-0045A - - - status not available Eurasian 201492214A1 - 201691031A1 - Patent Under examination Office** Published with search report in October 2015. Ecuador 2015-2066 # - - - Egypt 2100/2014 # - - - El Salvador 20150017587 # - - - European 2870160A 3087086A1 3087085A1 Application has not yet Patent Under examination Under examination entered European phase Office*** Amended claims (23 March 2105) Gulf 2013/24849 # - - - Cooperation Council ° India 2598/MUMNP/2014 - - - Awaiting for examination Indonesia P00201408047 # - - - Israel 236500A1 - 246064 - Under examination Japan 2015523365A 2016560857 2016541595 - Under examination Amended claims (01 November 2015) Malaysia PI2014003617 # - - - Mexico 2014015846A - - - Status not available Morocco 37659 # - - - 29

Patent 1 Patent 2 Patent 3 Patent 4

New Zealand 703064 # - - - Organisation 1201400575 # - - - Africaine de la Propriété Intellectuelle (OAPI) °° Pakistan 442/2013 # - - - Panama 90482-01 # - - - Paraguay 29361/2013 # - - - Peru 02042015A1 - - - Status not available Philippines 12014502862A1 - - - Status not available Republic of 1020150034698A - 20160101934A - Korea Request for examination (08 October 2015) Refused (10 November 2015) Singapore 11201408739V - 11201604482Q - Under examination South Africa 2014/09219 # - - - Thailand 1401007673 # - - - Ukraine 201413651 # - - - Uruguay 34888A 35918A - - Status not available Status not available USA 9,296,782 20150175625A1 20150175626A 20150150897A1 Pub. N°: 20140017198 Under examination Under examination Granted Expiry: 02 July 2033 20150175655A1 Under examination Venezuela 000831-2013 # - - - Viet Nam 42502 - - - Appl. N°: 1-2014-04304 Under examination

Notes: Cells with “–” indicate that no patent or patent application has been found in the INPADOC database. This may mean that no patent application has been filed, that the patent application has not been found (e.g. in the case of clerical error), or the patent application had not been published at the time of the search. Information in this Annex should therefore always be checked at the relevant Patent Office.

* African Regional Intellectual Property Organization (ARIPO): Botswana, Gambia, Ghana, Kenya, Lesotho, Liberia, Malawi, Mozambique, Namibia, Rwanda, São Tomé and Príncipe, Sierra Leone, Somalia, Sudan, Swaziland, Tanzania, Uganda, Zambia, Zimbabwe.

** Eurasian Patent Organization (EAPO): Armenia, Azerbaijan, Belarus, Kazakhstan, Kyrgyz Republic, Moldova, Russian

Federation, Tajikistan, Turkmenistan.

*** European Patent Office (EPO): designated contracting states: Albania, Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Liechtenstein, Lithuania, Luxembourg, Macedonia (former Yugoslav Republic of Macedonia), Malta, Monaco, Netherlands, Norway, Poland, Portugal, Romania, San Marino, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, United Kingdom; Extension states: Bosnia and Herzegovina, Montenegro.

° The Patent Office of the Cooperation Council for the Arab States of the Gulf (Gulf Cooperation Council or GCC) includes the following countries: Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, United Arab Emirates.

°° Organisation Africaine de la Propriété Intellectuelle (OAPI): Benin, Burkina Faso, Cameroon, Central African Republic, Chad, Comoros, Congo, Equatorial Guinea, Gabon, Guinea, Guinea Bissau, Ivory Coast, Mali, Mauritania, Niger, Senegal, Togo.

# Data source: Form 3, submitted to the Indian Patent Office on 26 April 2016.